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Background: The term Gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features have not been established yet., Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization., Results: Median overall survival (OS) was 15.5 months (interquartile range, 10.9-27.7) with a 2-years survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2-55.7); grade III: 15.9 months (11.4-26.3); grade IV: 10.4 months (8.8-14.4). By DNA methylation profiling (n=49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wildtype (n=31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n=19), pedHGG_A/B (n=6), and pedHGG_MYCN (n=5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wildtype subgroup, recurrent alterations in EGFR (n=10) and BCOR (n=9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wildtype subgroup TP53 alterations had a significant negative effect on OS., Conclusion: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements)., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Detection of the BRAF V600E mutation in pediatric low-grade glioma has been associated with a lower response to standard chemotherapy. In previous trials, dabrafenib (both as monotherapy and in combination with trametinib) has shown efficacy in recurrent pediatric low-grade glioma with BRAF V600 mutations, findings that warrant further evaluation of this combination as first-line therapy., Methods: In this phase 2 trial, patients with pediatric low-grade glioma with BRAF V600 mutations who were scheduled to receive first-line therapy were randomly assigned in a 2:1 ratio to receive dabrafenib plus trametinib or standard chemotherapy (carboplatin plus vincristine). The primary outcome was the independently assessed overall response (complete or partial response) according to the Response Assessment in Neuro-Oncology criteria. Also assessed were the clinical benefit (complete or partial response or stable disease for ≥24 weeks) and progression-free survival., Results: A total of 110 patients underwent randomization (73 to receive dabrafenib plus trametinib and 37 to receive standard chemotherapy). At a median follow-up of 18.9 months, an overall response occurred in 47% of the patients treated with dabrafenib plus trametinib and in 11% of those treated with chemotherapy (risk ratio, 4.31; 95% confidence interval [CI], 1.7 to 11.2; P<0.001). Clinical benefit was observed in 86% of the patients receiving dabrafenib plus trametinib and in 46% receiving chemotherapy (risk ratio, 1.88; 95% CI, 1.3 to 2.7). The median progression-free survival was significantly longer with dabrafenib plus trametinib than with chemotherapy (20.1 months vs. 7.4 months; hazard ratio, 0.31; 95% CI, 0.17 to 0.55; P<0.001). Grade 3 or higher adverse events occurred in 47% of the patients receiving dabrafenib plus trametinib and in 94% of those receiving chemotherapy., Conclusions: Among pediatric patients with low-grade glioma with BRAF V600 mutations, dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival, and a better safety profile than standard chemotherapy as first-line therapy. (Funded by Novartis; ClinicalTrials.gov number, NCT02684058.)., (Copyright © 2023 Massachusetts Medical Society.)

Purpose of the Report: Paediatric diffuse high-grade gliomas (PDHGG) are rare central nervous system neoplasms lacking effective therapeutic options. Molecular imaging of tumour metabolism might identify novel diagnostic/therapeutic targets. In this study, we evaluated the distribution and the dosimetry aspects of [ 64 Cu]CuCl 2 in PDHGG subjects, as copper is a key element in cellular metabolism whose turnover may be increased in tumour cells., Material and Methods: Paediatric patients with PDHGG were prospectively recruited. [ 64 Cu]CuCl 2 PET/CT was performed 1 h after tracer injection; if the scan was positive, it was repeated 24 and 72 h later. Lesion standardised uptake value (SUV) and target-to-background ratio (TBR) were calculated. Tumour and organ dosimetry were computed using the MIRD algorithm. Each patient underwent an MRI scan, including FLAIR, T2-weighted and post-contrast T1-weighted imaging., Results: Ten patients were enrolled (median age 9, range 6-16 years, 6 females). Diagnoses were diffuse midline gliomas (n = 8, 5 of which with H3K27 alterations) and diffuse hemispheric gliomas (n = 2). Six patients had visible tracer uptake (SUV: 1.0 ± 0.6 TBR: 5 ± 3.1). [ 64 Cu]CuCl 2 accumulation was always concordant with MRI contrast enhancement and was higher in the presence of radiological signs of necrosis. SUV and TBR progressively increased on the 24- and 72-h acquisitions (p < 0.05 and p < 0.01, respectively). The liver and the abdominal organs received the highest non-target dose., Conclusions: [ 64 Cu]CuCl 2 is a well-tolerated radiotracer with reasonably favourable dosimetric properties, showing selective uptake in tumour areas with visible contrast enhancement and necrosis, thus suggesting that blood-brain barrier damage is a pre-requisite for its distribution to the intracranial structures. Moreover, tracer uptake showed an accumulating trend over time. These characteristics could deserve further analysis, to determine whether this radiopharmaceutical might have a possible therapeutic role as well., (© 2022. The Author(s), under exclusive licence to World Molecular Imaging Society.)

Purpose: Our aim was to determine the main risk factors related to the occurrence of permanent alopecia in childhood medulloblastoma (MB) survivors., Methods: We retrospectively analyzed the clinical features of all consecutive MB survivors treated at our institute. We divided the patients into 3 groups depending on the craniospinal irradiation (CSI) dose received and defined permanent alopecia first in terms of the skin region affected (whole scalp and nape region), then on the basis of the toxicity degree (G). Any relationship between permanent alopecia and other characteristics was investigated by a univariate and multivariate analysis and Odds ratio (OR) with confidence interval (CI) was reported., Results: We included 41 patients with a mean10-year follow-up. High dose CSI resulted as an independent factor leading to permanent hair loss in both groups: alopecia of the whole scalp (G1 p-value 0.030, G2 p-value 0.003) and of the nape region (G1 p-value 0.038, G2 p-value 0.006). The posterior cranial fossa (PCF) boost volume and dose were not significant factors at multivariate analysis neither in permanent hair loss of the whole scalp nor only in the nuchal region., Conclusion: In pediatric patients with MB, the development of permanent alopecia seems to depend only on the CSI dose ≥ 36 Gy. Acute damage to the hair follicle is dose dependent, but in terms of late side effects, constant and homogeneous daily irradiation of a large volume may have a stronger effect than a higher but focal dose of radiotherapy., (© 2022. The Author(s).)

Background: To date, this is the only report showing with close and consecutive magnetic resonance images the extremely rapid response of two types of pediatric low-grade gliomas (PLGG) to vemurafenib and its impact on the surgical approach., Cases Presentation: We report two cases of symptomatic PLGG treated with vemurafenib, a BRAF inhibitor: in a 12-year-old girl it was used as first-line medical treatment, reducing the tumor by 45% within a month and stabilizing to 76% after a year; in a 3-year-old boy with no improvement after SIOP LGG 2004 Protocol, vemurafenib induced in only one week a 34% shrinkage and solved the hydrocephalus, avoiding surgical operation. DISCUSSION AND CONCLUSIONS: Our cases demonstrate how an early molecular diagnosis of BRAF mutations through the neurosurgical biopsy is essential to promptly start targeted therapies., whose effect can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae., (© 2022. The Author(s).)

Background: CNS germinoma, being marker-negative, are mainly diagnosed by histological examination. These tumors predominantly appear in the suprasellar and/or pineal region. In contrast to the suprasellar region, where biopsy is the standard procedure in case of a suspected germ-cell tumor to avoid mutilation to the endocrine structures, pineal tumors are more accessible to primary resection. We evaluated the perioperative course of patients with pineal germinoma who were diagnosed by primary biopsy or resection in the SIOP CNS GCT 96 trial. Methods: Overall, 235 patients had germinoma, with pineal localization in 113. The relationship between initial symptoms, tumor size, and postoperative complications was analyzed. Results: Of 111 evaluable patients, initial symptoms were headache (n = 98), hydrocephalus (n = 93), double vision (n = 62), Parinaud syndrome (n = 57), and papilledema (n = 44). There was no significant relationship between tumor size and primary symptoms. A total of 57 patients underwent primary resection and 54 underwent biopsy. Postoperative complications were reported in 43.2% of patients after resection and in 11.4% after biopsy (p < 0.008). Biopsy was significantly more commonly performed on larger tumors (p= 0.002). Conclusions: These results support the practice of biopsy over resection for histological confirmation of pineal germinoma.

Background: Growth hormone deficiency (GHD) is the first and most common endocrine complication in pediatric brain tumor survivors (BTS). GHD can occur due to the presence of the tumor itself, surgery, or cranial radiotherapy (CRT)., Aims: This study aimed to evaluate management and adherence to current guidelines of the Italian centers engaged in the diagnosis and follow-up of GHD patients with BTS., Methods: A multidisciplinary scientific board of pediatric endocrinologists, oncologists and radiologists with neuroimaging expertise discussed and reviewed the main issues relating to the management of GHD in pediatric BTS and developed a survey. The survey included questions relating to organizational aspects, risk factors, diagnosis, definition of stable disease, and treatment. The online survey was sent to an expanded panel of specialists dedicated to the care of pediatric BTS, distributed among the three specialty areas and throughout the country (23 Italian cities and 37 Centers)., Results: The online questionnaire was completed by 86.5% (32 out of 37) of the Centers involved. Most had experience in treating these patients, reporting that they follow more than 50 BTS patients per year. Responses were analyzed descriptively and aggregated by physician specialty. Overall, the results of the survey showed some important controversies in real life adherence to the current guidelines, with discrepancies between endocrinologists and oncologists in the definition of risk factors, diagnostic work-up, decision-making processes and safety. Furthermore, there was no agreement on the neuroimaging definition of stable oncological disease and how to manage growth hormone therapy in patients with residual tumor and GHD., Conclusions: The results of the first Italian national survey on the management of GHD in BTS highlighted the difference in management on some important issues. The time to start and stop rhGH treatment represent areas of major uncertainty. The definition of stable disease remains critical and represents a gap in knowledge that must be addressed within the international guidelines in order to increase height and to improve metabolic and quality of life outcomes in cancer survivors with GHD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Di Iorgi, Morana, Cappa, D’Incerti, Garrè, Grossi, Iughetti, Matarazzo, Parpagnoli, Pozzobon, Salerno, Sardi, Wasniewska, Zucchini, Rossi and Maghnie.)

Background: Little is known about risks associated with germline SUFU pathogenic variants (PVs) known as a cancer predisposition syndrome., Methods: To study tumour risks, we have analysed data of a large cohort of 45 unpublished patients with a germline SUFU PV completed with 127 previously published patients. To reduce the ascertainment bias due to index patient selection, the risk of tumours was evaluated in relatives with SUFU PV (89 patients) using the Nelson-Aalen estimator., Results: Overall, 117/172 (68%) SUFU PV carriers developed at least one tumour: medulloblastoma (MB) (86 patients), basal cell carcinoma (BCC) (25 patients), meningioma (20 patients) and gonadal tumours (11 patients). Thirty-three of them (28%) had multiple tumours. Median age at diagnosis of MB, gonadal tumour, first BCC and first meningioma were 1.5, 14, 40 and 44 years, respectively. Follow-up data were available for 160 patients (137 remained alive and 23 died). The cumulative incidence of tumours in relatives was 14.4% (95% CI 6.8 to 21.4), 18.2% (95% CI 9.7 to 25.9) and 44.1% (95% CI 29.7 to 55.5) at the age of 5, 20 and 50 years, respectively. The cumulative risk of an MB, gonadal tumour, BCC and meningioma at age 50 years was: 13.3% (95% CI 6 to 20.1), 4.6% (95% CI 0 to 9.7), 28.5% (95% CI 13.4 to 40.9) and 5.2% (95% CI 0 to 12), respectively. Sixty-four different PVs were reported across the entire SUFU gene and inherited in 73% of cases in which inheritance could be evaluated., Conclusion: Germline SUFU PV carriers have a life-long increased risk of tumours with a spectrum dominated by MB before the age of 5, gonadal tumours during adolescence and BCC and meningioma in adulthood, justifying fine-tuned surveillance programmes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Purpose of the Report: PET with 18F-DOPA can be used to evaluate grading and aggressiveness of pediatric cerebral gliomas. However, standard uptake parameters may underperform in circumscribed lesions and in diffuse pontine gliomas. In this study, we tested whether dynamic 18F-DOPA PET could overcome these limitations., Patients and Methods: Patients with available dynamic 18F-DOPA PET were included retrospectively. Static parameters (tumor/striatum ratio [T/S] and tumor/cortex ratio [T/N]) and dynamic ones, calculated on the tumor time activity curve (TAC), including time-to-peak (TTP), slope steepness, the ratio between tumor and striatum TAC steepness (dynamic slope ratio [DSR]), and TAC shape (accumulation vs plateau), were evaluated as predictors of high/low grading (HG and LG) and of progression-free survival and overall survival., Results: Fifteen patients were included; T/S, T/N, TTP, TAC slope steepness, and DSR were not significantly different between HG and LG. The accumulation TAC shape was more prevalent in the LG than in the HG group (75% vs 27%). On progression-free survival univariate analysis, TAC accumulation shape predicted longer survival (P < 0.001), whereas T/N and DSR showed borderline significance; on multivariate analyses, only TAC shape was retained (P < 0.01, Harrell C index, 0.93-0.95). On overall survival univariate analysis, T/N (P < 0.05), DSR (P < 0.05), and TAC "accumulating" shape predicted survival (P < 0.001); once more, only this last parameter was retained in the multivariate models (P < 0.05, Harrell C index, 0.86-0.89)., Conclusions: Dynamic 18F-DOPA PET analysis outperforms the static parameter evaluation in grading assessment and survival prediction. Evaluation of the curve shape is a simple-to-use parameter with strong predictive power., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

BRAF inhibitors, in recent years, have played a central role in the disease control of unresectable BRAF-mutated pediatric low-grade gliomas (LGGs). The aim of the study was to investigate the acute and long-term effects of vemurafenib on the lipid metabolism in children treated for an LGG. In our cohort, children treated with vemurafenib ( n = 6) exhibited alterations in lipid metabolism a few weeks after starting, as was demonstrated after 1 month ( n = 4) by the high plasma levels of the total cholesterol (TC = 221.5 ± 42.1 mg/dL), triglycerides (TG = 107.8 ± 44.4 mg/dL), and low-density lipoprotein (LDL = 139.5 ± 51.5 mg/dL). Despite dietary recommendations, the dyslipidemia persisted over time. The mean lipid levels of the TC (222.3 ± 34.7 mg/dL), TG (134.8 ± 83.6 mg/dL), and LDL (139.8 ± 46.9 mg/dL) were confirmed abnormal at the last follow-up (45 ± 27 months, n = 6). Vemurafenib could be associated with an increased risk of dyslipidemia. An accurate screening strategy in new clinical trials, and a multidisciplinary team, are required for the optimal management of unexpected adverse events, including dyslipidemia.

Background: More than 40% of patients with intracranial ependymoma need a salvage treatment within 5 years after diagnosis, and no standard treatment is available as yet. We report the outcome after first relapse of 64 patients treated within the 2nd AIEOP protocol., Methods: We considered relapse sites and treatments, that is, various combinations of complete/incomplete surgery, if followed by standard or hypofractionated radiotherapy (RT) ± chemotherapy (CT). Molecular analyses were available for 38/64 samples obtained at first diagnosis. Of the 64 cases, 55 were suitable for subsequent analyses., Results: The median follow-up was 147 months after diagnosis, 84 months after first relapse, 5-year EFS/OS were 26.2%/30.8% (median EFS/OS 13/32 months) after relapse. For patients with a local relapse (LR), the 5-year cumulative incidence of second LRs was 51.6%, with a 5-year event-specific probability of being LR-free of 40.0%. Tumor site/grade, need for shunting, age above/below 3 years, molecular subgroup at diagnosis, had no influence on outcomes. Due to variation in the RT dose/fractionation used and the subgroup sizes, it was not possible to assess the impact of the different RT modalities. Multivariable analyses identified completion of surgery, the absence of symptoms at relapse, and female sex as prognostically favorable. Tumors with a 1q gain carried a higher cumulative incidence of dissemination after first relapse., Conclusions: Survival after recurrence was significantly influenced by symptoms and completeness of surgery. Only a homogeneous protocol with well-posed, randomized questions could clarify the numerous issues, orient salvage treatment, and ameliorate prognosis for this group of patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Assessment of endothelial dysfunction in cancer survivors may have a role in the early identification of non-communicable diseases and cardiovascular late effects. Oncological therapies may impair endothelial function. Therefore, in patients such as childhood cancer survivors who could benefit from early cardioprotective pharmacological interventions, it is essential to monitor endothelial function, even if the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, as well as invasive and non-invasive tools with and without pharmacological stimuli have been studied. Human clinical studies that have examined lifestyle or cancer treatment protocols have yielded evidence showing the involvement of lipid and lipoprotein levels, glycemic control, blood pressure, adiposity, inflammation, and oxidative stress markers on the state of endothelial health and its role as an early indicator of cardiometabolic risk. However, with regards to pharmacological interventions, cautious interpretation of the result attained whilst monitoring the endothelial function is warranted due to methodological limitations and substantial heterogeneity of the results reported in the published studies. In this narrative review, an overview of evidence from human clinical trials examining the effects of cancer therapies on endothelial disease is provided together with a discussion of endothelial function assessment using the different non-invasive techniques available for researchers and clinicians, in recent years.

Atypical teratoid/rhabdoid tumors (AT/RTs) in the rhabdoid tumor predisposition syndromes are most often caused by germline mutations of the SMARCB1 gene located in chromosome 22q11.2. Although rarely, it can also result from the constitutional ring chromosome 22 (r22): during mitosis the ring chromosome may lead to an increased rate of somatic mutations, resulting in rhabdoid tumor predispositions when the tumor-suppressor gene SMARCB1 is involved. Individuals with r22 may present similar features as those with Phelan-McDermid syndrome (PMDS) due to 22q13.3 deletion, including the SHANK3 gene. Despite several reports on AT/RT in children with r22 and/or PMDS have been published, the role of constitutional r22 as new oncogenic mechanism for AT/RT is still under investigation. There is not a lot of data available on therapeutic and prognostic implications of r22 in AT/RT and PMDS. Herein, we present the first case of a child with constitutional r22, PMDS and AT/RT of the brain, who is a long term survivor and is been treated with growth hormone. We also describe an unexpected adverse reaction to midazolam., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Crocco, Panciroli, Milanaccio, Morerio, Verrico, Garrè, Di Iorgi and Capra.)

In children with cancer, the heterogeneity in ototoxicity occurrence after similar treatment suggests a role for genetic susceptibility. Using a genome-wide association study (GWAS) approach, we identified a genetic variant in TCERG1L (rs893507) to be associated with hearing loss in 390 non-cranial irradiated, cisplatin-treated children with cancer. These results were replicated in two independent, similarly treated cohorts (n = 192 and 188, respectively) (combined cohort: P = 5.3 × 10 -10 , OR 3.11, 95% CI 2.2-4.5). Modulating TCERG1L expression in cultured human cells revealed significantly altered cellular responses to cisplatin-induced cytokine secretion and toxicity. These results contribute to insights into the genetic and pathophysiological basis of cisplatin-induced ototoxicity., (© 2021. The Author(s).)

Neurofibromatosis type 1 (NF1) is a proteiform genetic condition caused by pathogenic variants in NF1 and characterized by a heterogeneous phenotypic presentation. Relevant genotype-phenotype correlations have recently emerged, but only few pertinent studies are available. We retrospectively reviewed clinical, instrumental, and genetic data from a cohort of 583 individuals meeting at least 1 diagnostic National Institutes of Health (NIH) criterion for NF1. Of these, 365 subjects fulfilled ≥2 NIH criteria, including 235 pediatric patients. Genetic testing was performed through cDNA-based sequencing, Next Generation Sequencing (NGS), and Multiplex Ligation-dependent Probe Amplification (MLPA). Uni- and multivariate statistical analysis was used to investigate genotype-phenotype correlations. Among patients fulfilling ≥ 2 NIH criteria, causative single nucleotide variants (SNVs) and copy number variations (CNVs) were detected in 267/365 (73.2%) and 20/365 (5.5%) cases. Missense variants negatively correlated with neurofibromas ( p = 0.005). Skeletal abnormalities were associated with whole gene deletions ( p = 0.05) and frameshift variants ( p = 0.006). The c.3721C>T; p.(R1241*) variant positively correlated with structural brain alterations ( p = 0.031), whereas Lisch nodules ( p = 0.05) and endocrinological disorders ( p = 0.043) were associated with the c.6855C>A; p.(Y2285*) variant. We identified novel NF1 genotype-phenotype correlations and provided an overview of known associations, supporting their potential relevance in the implementation of patient management.

To evaluate the contribution of 18 F-dihydroxyphenylalanine (DOPA) PET in association with conventional MRI in predicting treatment response and survival outcome of pediatric patients with diffuse intrinsic pontine gliomas (DIPGs). Methods: We retrospectively analyzed 19 children with newly diagnosed DIPGs who underwent 18 F-DOPA PET/CT and conventional MRI within one week of each other at admission and subsequent MRI follow-up. Following co-registration and fusion of PET and MRI, 18 F-DOPA uptake avidity and extent (PET tumor volume and uniformity) at admission, along with MRI indices including presence of ring contrast-enhancement, tumor volume at admission and at maximum response following first-line treatment, were evaluated and correlated with overall survival (OS). The association between 18 F-DOPA uptake tumor volume at admission and MRI tumor volume following treatment was evaluated. Statistics included Wilcoxon signed-rank and Mann-Whitney U tests, Kaplan-Meier OS curve and Cox analysis. Results: DIPGs with a 18 F-DOPA uptake Tumor/Striatum (T/S) ratio >1 presented an OS ≤ 12 months and lower degree of tumor volume reduction following treatment ( p = 0.001). On multivariate analysis, T/S ( p = 0.001), ring enhancement ( p = 0.01) and the degree of MRI tumor volume reduction ( p = 0.01) independently correlated with OS. In all patients, areas of increased 18 F-DOPA uptake overlapped with regions demonstrating more prominent residual components/lack of response following treatment. Conclusions: 18 F-DOPA PET provides useful information for evaluating the metabolism of DIPGs. T/S ratio is an independent predictor of outcome. 18 F-DOPA uptake extent delineates tumoral regions with a more aggressive biological behaviour, less sensitive to first line treatment., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background: Pediatric neurofibromatosis type 1 (NF1) patients rarely develop aggressive central nervous system tumors. Among high-grade gliomas (HGGs), histone mutant diffuse midline gliomas (DMGs H3 K27M-mutant) have exceptionally been reported. The aim of this retrospectives single-center study was to compare the clinical behavior of DMGs H3 K27M-mutant and non-histone mutant midline HGGs in NF1 vs. non-syndromic children and to report imaging features of NF1 HGGs. Method: We conducted a retrospective review of cerebral DMGs H3 K27M-mutant or non-histone mutant HGGs in 18 patients with or without NF1 followed at our institution between 2010 and 2018. Differences in outcomes, notably progression-free survival (PFS) and overall survival (OS), were evaluated. Results: Two patients were identified with genetically confirmed diagnosis of NF1 and cerebral HGGs (one DMG H3 K27M-mutant and one histone wild type). Both subjects presented with midline mass lesions with imaging features of aggressive biological activity on advanced MRI or amino-acid PET. During the same time period, 16 non-NF1 patients (11 subjects with DMGs H3 K27M-mutant and 5 with non-histone mutant midline HGGs) were treated at our institution. The two patients with NF1 and HGGs presented a PFS of 3 months and an OS of 5 and 7 months. Median PFS and OS of children without NF1 were respectively 6 and 10 months in DMGs H3 K27M-mutant, and 6 and 11 months in H3 K27M wild-type tumors. Seventy-five percent of subjects with non-NF1 HGGs presented a PFS >4 months compared to 0% in NF1 patients. The 8-month OS of patients with non-NF1 HGGs was 81% compared to 0% in NF1 patients. Conclusions: Cerebral HGGs arising in midline structures rarely occur in pediatric patients with NF1 and present with extremely poor prognosis, worse than HGGs developing in non-NF1 patients, independent of the presence or absence of H3 K27M mutation. Imaging features of aggressive biological activity on advanced MRI or amino-acid PET imaging suggest prompt neuropathological and molecular investigations., (Copyright © 2020 Garibotto, Madia, Milanaccio, Verrico, Piccardo, Tortora, Piatelli, Diana, Capra, Garrè, Rossi and Morana.)

Background: Over the last decades, significant advancements have been achieved in the treatment of pediatric brain tumors as a result of radiation therapy (RT). With the increasing diffusion of this treatment, iatrogenic damage to cerebrovascular tissues contouring the radiation target volume has become the subject of debate, especially radiation-induced moyamoya syndrome (RIMS)., Methods: A systematic literature search was performed on the association between moyamoya vasculopathy and cranial irradiation in children. Large case series of patients with moyamoya were analyzed and clinicoradiologic data were collected reviewing pediatric patients treated with RT for primary brain tumors at our institution., Results: The risk of developing RIMS is higher in younger children, in patients with optic pathway glioma, and in those receiving higher radiation doses. Headache is the most common presenting symptom and cerebral infarction is frequent. The preferred surgical techniques were pial synangiosis and encephaloduroarteriosynangiosis. In our case series, surgical revascularization led to neovascularization, with clinical improvement or stability in all patients. Medical therapy did not significantly affect the clinical course., Conclusions: Pediatric patients receiving involved field RT for the treatment of brain tumors have an increased risk of developing RIMS. Prompt diagnosis and early surgical revascularization play a pivotal role in decreasing the clinical impact of this complication. The use of new techniques, such as the intensity-modulated RT, and the increasing dose saving for the organs at risk, are essential to prevent iatrogenic vasculopathy. The combination of appropriate medical therapy and surgery will improve patient management and clinical outcome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To detect the presence of antipituitary (APA) and antihypothalamus antibodies (AHA) in subjects treated for brain cancers, and to evaluate their potential association with pituitary dysfunction. Methods: We evaluated 63 patients with craniopharyngioma, glioma, and germinoma treated with surgery and/or radiotherapy and/or chemotherapy at a median age of 13 years. Forty-one had multiple pituitary hormone deficiencies (MPHD), six had a single pituitary defect. GH was the most common defect (65.1%), followed by AVP (61.9%), TSH (57.1%), ACTH (49.2%), and gonadotropin (38.1%). APA and AHA were evaluated by simple indirect immunofluorescence method indirect immunofluorescence in patients and in 50 healthy controls. Results: Circulating APA and/or AHA were found in 31 subjects (49.2%) and in none of the healthy controls. In particular, 25 subjects out of 31 were APA (80.6%), 26 were AHA (83.90%), and 20 were both APA and AHA (64.5%). Nine patients APA and/or AHA have craniopharyngioma (29%), seven (22.6%) have glioma, and 15 (48.4%) have germinoma. Patients with craniopharyngioma were positive for at least one antibody in 39.1% compared to 33.3% of patients with glioma and to 78.9% of those with germinoma with an analogous distribution for APA and AHA between the three tumors. The presence of APA or AHA and of both APA and AHA was significantly increased in patients with germinoma. The presence of APA ( P = 0.001) and their titers ( P = 0.001) was significantly associated with the type of tumor in the following order: germinomas, craniopharyngiomas, and gliomas; an analogous distribution was observed for the presence of AHA ( P = 0.002) and their titers ( P = 0.012). In addition, we found a significant association between radiotherapy and APA ( P = 0.03). Conclusions: Brain tumors especially germinoma are associated with the development of hypothalamic-pituitary antibodies and pituitary defects. The correct interpretation of APA/AHA antibodies is essential to avoid a misdiagnosis of an autoimmune infundibulo-neurohypophysitis or pituitary hypophysitis in patients with germinoma., (Copyright © 2020 Patti, Calandra, De Bellis, Gallizia, Crocco, Napoli, Allegri, Thiabat, Bellastella, Maiorino, Garrè, Parodi, Maghnie and di Iorgi.)

In cancer, recurrent somatic single-nucleotide variants-which are rare in most paediatric cancers-are confined largely to protein-coding genes 1-3 . Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5' splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5' cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2 and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Purpose: The aim of this study was to investigate MRI-derived diffusion weighted imaging (DWI), 1 H-MR spectroscopy ( 1 H-MRS) and arterial spin labeling (ASL) perfusion imaging in comparison with 18 F-dihydroxyphenylalanine (DOPA) PET with respect to diagnostic evaluation of pediatric diffuse midline gliomas (DMG) H3K27M-mutant and wild-type., Methods: We retrospectively analyzed 22 pediatric patients with DMG histologically proved and molecularly classified as H3K27M-mutant (12 subjects) and wild-type (10 subjects) who underwent DWI, 1 H-MRS, and ASL performed within 2 weeks of 18 F-DOPA PET. DWI-derived relative minimum apparent diffusion coefficient (rADC min), 1 H-MRS data [choline/N-acetylaspartate (Cho/NAA), choline/creatine (Cho/Cr), and presence of lactate] and relative ASL-derived cerebral blood flow max (rCBF max) were compared with 18 F-DOPA uptake Tumor/Normal tissue (T/N) and Tumor/Striatum (T/S) ratios, and correlated with histological and molecular features of DMG. Statistics included Pearson's chi-square and Mann-Whitney U tests, Spearman's rank correlation and receiver operating characteristic (ROC) analysis., Results: The highest degrees of correlation among different techniques were found between T/S, rADC min and Cho/NAA ratio (p < 0.01), and between rCBF max and rADC min (p < 0.01). Significant differences between histologically classified low- and high-grade DMG, independently of H3K27M-mutation, were found among all imaging techniques (p ≤ 0.02). Significant differences in terms of rCBF max, rADC min, Cho/NAA and 18 F-DOPA uptake were also found between molecularly classified mutant and wild-type DMG (p ≤ 0.02), even though wild-type DMG included low-grade astrocytomas, not present among mutant DMG. When comparing only histologically defined high-grade mutant and wild-type DMG, only the 18 F-DOPA PET data T/S demonstrated statistically significant differences independently of histology (p < 0.003). ROC analysis demonstrated that T/S ratio was the best parameter for differentiating mutant from wild-type DMG (AUC 0.94, p < 0.001)., Conclusions: Advanced MRI and 18 F-DOPA PET characteristics of DMG depend on histological features; however, 18 F-DOPA PET-T/S was the only parameter able to discriminate H3K27M-mutant from wild-type DMG independently of histology.

Background: Survival rates after childhood cancer now reach nearly 80% in developed countries. However, treatments that lead to survival and cure can cause serious adverse effects with lifelong negative impacts on survivor quality of life. Hearing impairment is a common adverse effect in children treated with cisplatin-based chemotherapy or cranial radiotherapy. Ototoxicity can extend from high-tone hearing impairment to involvement of speech frequencies. Hearing impairment can impede speech and language and neurocognitive development. Although treatment-related risk factors for hearing loss following childhood cancer treatment have been identified, the individual variability in toxicity of adverse effects after similar treatment between childhood cancer patients suggests a role for genetic susceptibility. Currently, 12 candidate gene approach studies have been performed to identify polymorphisms predisposing to platinum-induced ototoxicity in children being treated for cancer. However, results were inconsistent and most studies were underpowered and/or lacked replication., Objective: We describe the design of the PanCareLIFE consortium's work packages that address the genetic susceptibility of platinum-induced ototoxicity., Methods: As a part of the PanCareLIFE study within the framework of the PanCare consortium, we addressed genetic susceptibility of treatment-induced ototoxicity during and after childhood cancer treatment in a large European cohort by a candidate gene approach and a genome-wide association screening., Results: This study included 1124 survivors treated with cisplatin, carboplatin, or cranial radiotherapy for childhood cancer, resulting in the largest clinical European cohort assembled for this late effect to date. Within this large cohort we defined a group of 598 cisplatin-treated childhood cancer patients not confounded by cranial radiotherapy. The PanCareLIFE initiative provided, for the first time, a unique opportunity to confirm already identified determinants for hearing impairment during childhood cancer using a candidate gene approach and set up the first international genome-wide association study of cisplatin-induced direct ototoxicity in childhood cancer patients to identify novel allelic variants. Results will be validated in an independent replication cohort. Patient recruitment started in January 2015 and final inclusion was October 2017. We are currently performing the analyses and the first results are expected by the end of 2019 or the beginning of 2020., Conclusions: Genetic factors identified as part of this pan-European project, PanCareLIFE, may contribute to future risk prediction models that can be incorporated in future clinical trials of platinum-based therapies for cancer and may help with the development of prevention strategies., International Registered Report Identifier (irrid): DERR1-10.2196/11868., (©Eva Clemens, Annelot JM Meijer, Linda Broer, Thorsten Langer, Anne-Lotte LF van der Kooi, André G Uitterlinden, Andrica de Vries, Claudia E Kuehni, Maria L Garrè, Tomas Kepak, Jarmila Kruseova, Jeanette F Winther, Leontien C Kremer, Eline van Dulmen-den Broeder, Wim JE Tissing, Catherine Rechnitzer, Line Kenborg, Henrik Hasle, Desiree Grabow, Ross Parfitt, Harald Binder, Bruce C Carleton, Julianne Byrne, Peter Kaatsch, Antoinette am Zehnhoff-Dinnesen, Oliver Zolk, Marry M van den Heuvel-Eibrink. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 19.03.2019.)

Background: Proton therapy has proven to be effective and safe in the treatment of radioresistant skull base tumors such as chordomas. Thanks to the peculiar physical properties of the proton beam, radiation energy is delivered in a narrow space called the Bragg peak and the surrounding normal tissues receive a minimal amount of the radiation dose. This is important to lower the risk of radiation-induced damage, especially in children. However, local adverse effects in proximity to the target volume may occur. In particular, the development of moyamoya syndrome (MMS) has been rarely reported in children receiving proton beam therapy for brain tumors., Case Description: We report on a child who developed rapidly progressive MMS after proton beam therapy for a clivus chordoma. A combined indirect revascularization procedure by encephalo-duro-arterio-synangiosis and encephalo-myo-synangiosis was performed with good neuroradiologic and clinical outcome., Conclusions: Regardless of the presence of known risk factors for MMS, strict neuroimaging surveillance is indicated in all patients treated with radiotherapy including those receiving proton beam therapy. We suggest that an early revascularization procedure should be considered in patients with worsening symptoms and/or sign of neuroradiologic progression of cerebral vasculopathy. This management of MMS could lower the risk of permanent neurologic deficits and improve patients' quality of life., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Introduction: Advances in paediatric oncology led to the increase in long-term survival, revealing the burden of therapy-related long-term side effects. We evaluated overall and cause-specific mortality in a large cohort of Italian childhood cancer survivors (CCSs) and adolescent cancer survivors identified through the off-therapy registry., Materials and Methods: CCSs alive 5 years after cancer diagnosis occurring between 1960 and 1999 were eligible; the last follow-up was between 2011 and 2014. Outcomes were reported as standardised mortality ratios (SMRs) and absolute excess risks (AERs)., Results: Among 12,214 CCSs, 1113 (9.1%) deaths occurred. Survival at 35 years since diagnosis was 87% (95% confidence interval [CI]: 86-88) and at 45 years was 81% (95% CI: 77-84). CCSs had an 11-fold increased risk of death (SMR 95% CI: 10.7-12), corresponding to an AER of 48 (95% CI: 45-51). Mortality decreased by 60% for survivors treated most recently (1990-1999). The most frequent causes of death were recurrence of the original cancer (56%), a subsequent neoplasm (19%) and cardiovascular diseases (5.8%). Among those who survived at least 15 years after diagnosis, a secondary malignancy was the leading cause of death., Conclusions: This study confirms the impact of recent advances in anticancer therapy in reducing mortality, mainly attributable to recurrence but also to other causes. However, overall mortality continues to be higher than in the general population. A long-term follow-up is needed to prevent late mortality due to secondary neoplasms and non-neoplastic causes in CCSs., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: The aims of patients' radiological surveillance are to: ascertain relapse; apply second-line therapy; accrue patients in phase 1/2 protocols if second-line therapy is not standardized/curative; and assess/treat iatrogenic effects. To lessen the emotional and socioeconomic burdens for patients and families, we ideally need to establish whether scheduled radiological surveillance gives patients a better outcome than waiting for symptoms and signs to appear., Methods: We analyzed a prospective series of 160 newly-diagnosed and treated pediatric/adolescent patients with intracranial ependymoma, comparing patients with recurrent disease identified on scheduled MRI (the RECPT group; 34 cases) with those showing signs/symptoms of recurrent disease (the SYMPPT group; 16 cases). The median follow-up was 67 months., Results: No significant differences emerged between the two groups in terms of gender, age, tumor grade/site, shunting, residual disease, or type of relapse (local, distant, or concomitant). The time to relapse (median 19 months; range 5-104) and the MRI follow-up intervals did not differ between the SYMPPT and RECPT groups. The presence of signs/symptoms was an unfavorable factor for overall survival (OS) after recurrence (5-year OS: 8% vs. 37%, p = 0.001). On multivariable analysis, an adjusted model confirmed a significantly worse OS in the SYMPPT than in the RECPT patients., Conclusions: Symptomatic relapses carried a significantly worse survival for ependymoma patients than recurrences detected by MRI alone. It would therefore be desirable to identify recurrences before symptoms develop. Radiological follow-up should be retained in ependymoma patient surveillance because there is a chance of salvage treatment for relapses found on MRI.

It has been reported that the ATM kinase inhibitor KU60019 preferentially radiosensitizes orthotopic high grade gliomas (HGG) driven by established U87 and U1242 cell lines bearing specific TP53 mutations. We wished to determine whether those results could be extended to tumors driven by primary glioma initiating cells (GIC) that closely mimic clinical tumors. Orthotopic HGG were developed in immunodeficient non-obese diabetic-severe combined immunodeficient (NOD-SCID) mice by intracranial injection of primary GIC isolated from the adult glioblastoma COMI (acronym of patient's name) and the pediatric anaplastic astrocytoma 239/12. Similar to the clinical tumors of origin, the orthotopic tumors COMI and 239/12 displayed different growth properties with a voluminous expansive lesion that exerted considerable mass effect on the adjacent structures and an infiltrating, gliomatosis-like growth pattern with limited compressive attitude, respectively. Significant elongations of median animal survival bearing the adult COMI tumor was observed after one KU60019 convection enhanced delivery followed by total 7.5 Gy of ionizing radiation delivered in fifteen 0.5 Gy fractions, as compared to animals treated with vehicle + ionizing radiation (105 vs 89 days; ratio: 0.847; 95% CI of ratio 0.4969 to 1.198; P:0.0417) [ARRIVE 16]. Similarly, a trend to increased median survival was observed with the radiosensitized pediatric tumor 239/12 (186 vs 167 days; ratio: 0.8978; 95% CI of ratio: 0.5352 to 1.260; P: 0.0891) [ARRIVE 16]. Our results indicate that radiosensitization by KU60019 is effective towards different orthotopic gliomas that faithfully mimic the clinical tumors and that multiple GIC-based animal models may be essential to develop novel therapeutic protocols for HGG transferable to the clinics.

Background: Moyamoya disease (MMD) is a cerebrovascular disorder characterized by the progressive occlusion of the supraclinoid internal carotid artery (ICA), resulting in the formation of an abnormal cerebral vascular network. When MMD occurs in association with an underlying medical condition, including some distinctive genetic disorders, it is named moyamoya syndrome (MMS). The discrimination between MMD and MMS has been validated by recent genetic researches and international reviews. Similarly to patients suffering from MMD, patients with MMS generally become symptomatic because of ischemic complications, which lead to hemiparesis, transient ischemic events, seizures, and sensory symptoms. RASopathies are a group of neurodevelopmental disorders that can be associated with MMS., Results: We retrospectively reviewed 18 RASopathy patients with MMS treated at our institution from 2000 to 2015 (16 neurofibromatosis type 1, 1 Costello syndrome, and 1 Schimmelpenning syndrome). Here, we report clinical data, performed surgical procedures, and clinic-radiological outcome of these patients. Most of them received both indirect revascularization and medical therapy., Conclusions: At the moment, there are no univocal recommendations on which of these two treatment strategies is the treatment of choice in patients with RASopathies and MMS. We suggest that patients with a good overall prognosis (primarily depending on the distinctive underlying genetic disorder) and initial cerebrovascular disease could benefit from a prophylactic surgical revascularization, in order to prevent the cognitive impairment due to the progression of the vasculopathy.

The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF&#95;V600E or NF1 mutation) had significantly more CD8 + tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The aim of this study was to compare arterial spin labeling (ASL) and dynamic susceptibility contrast (DSC) MRI perfusion with respect to diagnostic performance in tumor grading in pediatric patients with low- and high-grade astrocytic tumors (AT)., Methods: We retrospectively analyzed 37 children with histologically proven treatment naive low- and high-grade AT who underwent concomitant pre-operative ASL and DSC MRI perfusion. Studies were performed on a 1.5 T scanner, and a pulsed technique was used for ASL. DSC data were post-processed with a leakage correction software. Normalization of tumor perfusion parameters was performed with contralateral normal appearing gray matter. Normalized cerebral blood volume (nCBV) values in the most perfused area of each neoplasm were compared with normalized DSC-derived cerebral blood flow (nDSC-CBF) and ASL-derived cerebral blood flow (nASL-CBF) data, and correlated with WHO tumor grade. Statistics included Pearson's chi-square and Mann-Whitney U tests, Spearman's rank correlation, and receiver operating characteristic (ROC) analysis., Results: A significant correlation was demonstrated between DSC and ASL data (p < 0.001). Significant differences in terms of DSC and ASL data were found between low- and high-grade AT (p < 0.001). ROC analysis demonstrated similar performances between all parameters in predicting tumor grade (nCBV: AUC 0.96, p < 0.001; nDSC-CBF: AUC 0.98, p < 0.001; nASL-CBF: AUC 0.96, p < 0.001)., Conclusions: Normalized pulsed ASL performed with a 1.5 T scanner provides comparable results to DSC MRI perfusion in pediatric AT and may allow distinction between high- and low-grade AT.

Purpose: The role of T2*-based MR imaging in intracranial germ cell tumors (GCTs) has not been fully elucidated. The aim of this study was to evaluate the susceptibility-weighted imaging (SWI) or T2* gradient echo (GRE) features of germinomas and non-germinomatous germ cell tumors (NGGCTs) in midline and off-midline locations., Methods: We retrospectively evaluated all consecutive pediatric patients referred to our institution between 2005 and 2016, for newly diagnosed, treatment-naïve intracranial GCT, who underwent MRI, including T2*-based MR imaging (T2* GRE sequences or SWI). Standard pre- and post-contrast T1- and T2-weighted imaging characteristics along with T2*-based MR imaging features of all lesions were evaluated. Diagnosis was performed in accordance with the SIOP CNS GCT protocol criteria., Results: Twenty-four subjects met the inclusion criteria (17 males and 7 females). There were 17 patients with germinomas, including 5 basal ganglia primaries, and 7 patients with secreting NGGCT. All off-midline germinomas presented with SWI or GRE hypointensity; among midline GCT, all NGGCTs showed SWI or GRE hypointensity whereas all but one pure germinoma were isointense or hyperintense to normal parenchyma. A significant difference emerged on T2*-based MR imaging among midline germinomas, NGGCTs, and off-midline germinomas (p < 0.001)., Conclusion: Assessment of the SWI or GRE characteristics of intracranial GCT may potentially assist in differentiating pure germinomas from NGGCT and in the characterization of basal ganglia involvement. T2*-based MR imaging is recommended in case of suspected intracranial GCT.

Atypical choroid plexus papillomas can metastasize in the form of leptomeningeal seeding. Postoperative chemotherapy is the recommended first-line treatment when gross-total removal is not achieved or in cases of disseminated disease. Here the authors report on 2 children with atypical choroid plexus papillomas and MRI findings of diffuse leptomeningeal enhancement at diagnosis, later presenting with spontaneous resolution of the leptomeningeal involvement after removal of the primary lesions. Observations in this report expand our knowledge about the natural history and biological behavior of these tumors and highlight the role of close neuroimaging surveillance in the management of atypical choroid plexus papillomas in cases with MRI evidence of diffuse leptomeningeal enhancement at presentation.

Diffusion weighted imaging (DWI) has an established role in primary CNS embryonal tumor (ET) characterization; however, its diagnostic utility in detecting relapse has never been determined. We aimed to compare DWI and conventional MRI sensitivity in CNS ET recurrence detection, and to evaluate the DWI properties of contrast-enhancing radiation induced lesions (RIL). Fifty-six patients with CNS ET (25 with disease relapse, 6 with RIL and 25 with neither disease relapse nor RIL) were retrospectively evaluated with DWI, conventional MRI (including both T2/FLAIR and post-contrast images), or contrast-enhanced MR imaging (CE-MRI) alone. MRI studies were independently reviewed by two neuroradiologists for detection and localization of potential brain relapses. Sensitivity for focal relapse detection was calculated for each image set on a lesion-by-lesion basis. A descriptive per subject analysis was also performed. Evaluation of follow-up MRI studies served as standard of reference. Focal recurrence detection sensitivity of DWI (96%) was significantly higher than conventional MRI (77%) and CE-MRI alone (51%) (p=0.0003 and p<0.0001). On per subject analysis there were not missed diagnoses for DWI. At the time of DWI relapse detection, conventional MRI missed 2 diagnoses, and CE-MRI 8. Analysis of medulloblastoma relapses revealed that DWI identified a higher number of focal lesions than CE-MRI in subjects with classic variant. All but one RIL did not show restricted diffusion. In conclusion, DWI is a valuable complementary technique allowing for improved detection of focal relapse in CNS ET patients, particularly in children with classic medulloblastoma, and may assist in differentiating recurrence from RIL., Competing Interests: CONFLICTS OF INTEREST The authors declare they have no conflicts of interest.

Background: This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III)., Methods: WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone., Results: From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable., Conclusions: In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports., (© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Medulloblastoma accounts for 15-20% of childhood nervous system tumours. The risk of dying was reduced by 30% in the last twenty years. Patients are divided in risk strata according to post-surgical disease, dissemination, histology and some molecular features such as WNT subgroup and MYC status. Sixty to 70% of patients older than 3 years are assigned to the average-risk group. High-risk patients include those with disseminated and/or residual disease, large cell and/or anaplastic histotypes, MYC genes amplification. Current and currently planned clinical trials will: (1) evaluate the feasibility of reducing both the dose of craniospinal irradiation and the volume of the posterior fossa radiotherapy (RT) for those patients at low biologic risk, commonly identified as those having a medulloblastoma of the WNT subgroup; (2) determine whether intensification of chemotherapy (CT) or irradiation can improve outcome in patients with high-risk disease; (3) find target therapies allowing tailored therapies especially for relapsing patients and those with higher biological risk., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: The use of helical tomotherapy (HT) for craniospinal irradiation (CSI) in pediatric patients remains an issue of discussion. In this study, we evaluated the integral dose (ID) to organs at risk (OARs) and to the whole body delivered with conventional 3-dimensional conformal radiotherapy (3D-CRT) and HT for pediatric patients and made a comparison according to different whole body volumes., Methods: We selected 10 pediatric patients with different body volumes and of different ages undergoing CSI. Plans for 3D-CRT and HT were developed for each patient. The ID to OARs and to the whole body were compared and statistical analyses were performed to determine differences., Results: We noticed that variations of ID depend on the different anatomical location of the organs relatively to the target, with lower ID to OARs opposed to the target and increased ID to lateral organs: ID tomotherapy/3D-CRT ratio was higher in lungs, kidneys, and mammary region, while it was lower in heart, liver, thyroid, and esophagus. The ID of the body increased with large volumes both in HT and in 3D-CRT plans, but in tomotherapy plans ID increased significantly more with large volumes than with small ones., Conclusions: While there are no differences in using tomotherapy or 3D-CRT with small body volumes, we found a difference with large volumes (≥20,000 mL vs ≤20,000 mL). Therefore, for very small patients, the use of intensity-modulated radiotherapy provided with tomotherapy to reduce the dose to OARs can be reconsidered.